Process for preparing cyclic polyethers

ABSTRACT

A method for the producing cyclic polyether structures at room temperature, in high yield and in a convergent manner, that may be applied to the synthesis of gambierol and ciguatoxin, without using an excessive amount of phosphate compound, alkylborane and cyclic ketene acetal phosphate are subjected to cross-coupling in the presence of a basic aqueous solution using palladium [1,1&#39;-bis(diphenylphosphino)ferrocene] chloride as a catalyst.

TECHNICAL FIELD

The invention of the present application relates to a method forproducing cyclic polyether compounds. More particularly, the inventionof the present application relates to a method for producing cyclicpolyethers that may be used as a starting material for the synthesis ofnatural substances such as gambierol, at room temperature without usingexcess phosphate compounds.

BACKGROUND OF THE INVENTION

It has been known that marine polycyclic ethers such as ciguatoxin andgambierol act as neurotoxins and exist in fish and shellfish, causingfood poisoning and red tide that deadens fish. Particularly, gambierol(compound I) is a toxin isolated from a dinoflagellate, Gambierdiscustoxicus, and is known to have a high toxicity of LD₅₀ of 50 μg/kg (mice;i.p.). The complicated steric structure of gambierol has been studied indetail using NMR and chiral anisotropic reagents (J. Am. Chem. Soc.1993, 115, 361-362; Tetrahedron Lett. 1998, 39, 97-100)

However, because obtaining and separating natural substances such asgambierol is very difficult, detailed mechanisms of the actions of suchsubstances at the molecular level is yet unknown. Therefore, in order tounravel the mechanism by which natural substances act as food poisoningtoxins, or to develop novel methods for the detection of naturalsubstances, a practical method for supplying such substances in quantityis thought to be essential.

The inventors have found and reported an easy method for the synthesisof giant compounds with complicated structures and molecular weights ofover 1,000, in small numbers of steps, wherein alkylborane is subjectedto cross-coupling with cyclic enol triflate using a palladium (O)catalyst (Tetrahedron Letters 39, 1998, 9027). Further, the inventorshave found and provided a method for the synthesis of cyclic polyetherstructures in a convergent manner, which may be applied to large cycliccompounds with seven or more rings by cross-coupling alkylborane andcyclic enol phosphate in the presence of a basic aqueous solution usingPd(PPh₃)₄ as a catalyst (Japanese Patent Application No. 12277/2000).

However, both of those methods require the use of excess phosphatecompounds and relatively high temperatures are necessary to obtain theproduct in high yield, making the method inefficient. Hence, a novelmethod for the production of cyclic polyether compounds that proceeds atlow temperature and gives a high reaction yield was in demand.

The coupling reaction using a palladium catalyst (Suzuki couplingreaction) may be one of the most useful methods in organic synthesis forthe production of carbon-carbon bonds. However, there are few reports onroom temperature Suzuki coupling reactions (J. Chem. Soc., Chem. Commun.1994, 2395; Tetrahedron 1997, 53, 15123-15134).

The invention of the present application has been achieved under theaforementioned circumstances and its object is to solve the problems ofthe prior art by providing a method for the synthesis of cyclicpolyether structures at room temperature, in high yield and in aconvergent manner, which may be applied to the synthesis of gambieroland ciguatoxin without the use of excess phosphate compounds.

DISCLOSURE OF THE INVENTION

In order to solve the above-described problems, the invention of thepresent application firstly provides A method for producing cyclicpolyether compounds, comprising the cross-coupling of alkylborane andcyclic ketene acetal phosphate in the presence of a basic aqueoussolution using palladium [1,1′-bis(diphenylphosphino)ferrocene] chlorideas a catalyst.

Secondly, the invention of the present application provides the methodfor producing cyclic polyether compounds, wherein a starting materialfor alkylborane and a reagent used for producing alkylborane is added tothe reaction system prior to the reaction, thereby producing alkylboranein situ and cross-coupling with cyclic ketene acetal phosphate in thepresence of a basic aqueous solution using palladium[1,1′-bis(diphenylphosphino)ferrocene] chloride as a catalyst; thirdly,the present invention provides the method for producing cyclic polyethercompounds, wherein alkylborane is obtained by the hydroboration ofexo-olefin with 9-BBN.

Fourthly the invention of the present application provides the methodfor producing cyclic polyether compounds, wherein the basic aqueoussolution is an aqueous solution of NaHCO₃.

Further, fifthly, the present invention provides the method forproducing cyclic polyether compounds, wherein 1 to 2 equivalents ofcyclic ketene acetal phosphate is added to 1 equivalent of alkylborane.

BEST MODE FOR CARRYING OUT THE INVENTION

The method for producing cyclic polyether of the present invention isexemplified by scheme (1).

Thus, in the method for synthesizing cyclic polyether of the presentinvention, alkylborane (compound (II)) and cyclic ketene acetalphosphate (compound (III)) are subjected to a cross-coupling reaction inthe presence of a basic aqueous solution using palladium[1,1′-bis(diphenylphosphino)ferrocene]chloride (hereinafter, referred toas “PdCl₂ (dppf)”) as a catalyst.

In the method for synthesizing cyclic polyether of the presentinvention, aqueous solutions of various basic substances such as NaOH,Cs₂CO₃and K₃PO₄may be listed as examples of the basic aqueous solution;aqueous solution of NaHCO₃ is preferable, since the product may beobtained in high yield. Although the amount of the basic aqueoussolution used is not particularly limited, using 3 equivalents to theexo-olefin is preferable since high yield may be obtained.

Further, the reaction temperature in not particularly limited either; inthe present method for the synthesis of cyclic polyethers, the reactionyield is high even at room temperature.

Regarding the starting material, alkylborane, those of variousstructures may be used; as shown in scheme (2), compounds prepared bythe hydroboration of oxo-olefins with 9-BBN, as disclosed in literature,are preferred.

Conditions for such synthesis may be selected from various commonmethods. For example, the amount of 9-BBN added may be 2 to 3equivalents for one equivalent of exo-olefin. Solvents maybe selectedfrom various organic solvents; THF is preferable since the startingmaterials, the product and 9-BBN are highly soluble therein. Further,the reaction temperature may be from room temperature to 50° C. It goeswithout saying that the alkylborane used in the present method may beprepared under conditions other than those described above.

The exo-olefin may be selected taking in consideration the structure ofthe aimed product that is to be synthesized, and the reaction route bywhich the aimed product is prepared; an examples would be compound(IIa).

The above exo-olefin may be synthesized from alcohol by methods such asthe one exemplified in scheme (3). It goes without saying that ifavailable, a commercial substance may be used, as well.

As described in the Examples to follow, the cyclic ketene acetalphosphate used in the present method for producing cyclic polyethers maybe of various structures having a dihydropyran structure; each compoundmay be synthesized by known methods from the corresponding lactone.

In the present method for producing cyclic polyether compounds, any kindof reaction solvent may be used, as long as decomposition or the likedoes not occur under the reaction conditions: DMF is especiallypreferable. Needless to say, various solvents such as THF, methanol,acetone and water may be used for the purifying process and intermediatesteps.

The reaction temperature may vary for each starting material and solventcondition; however, in the present method for producing cyclicpolyethers, by using PdCl₂ (dppf) as a catalyst, cyclic polyethers maybe obtained in high yield even at room temperature.

Furthermore, in the invention of the present application, the reactionfor preparing alkylborane from exo-olefin may be carried out in situ inthe reaction system where the cross-coupling of cyclic ketene acetalphosphate in the presence of a basic aqueous solution using PdCl₂ (dppf)as a catalyst takes place For example, exo-olefin and a reagent such as9-BDN are added to a reaction vessel together with the cyclic keteneacetal phosphate, the basic aqueous solution and the PdCl₂ (dppf)catalyst to obtain a cyclic polyether compound. In the reaction system,alkylborane is first produced by the hydroboration of exo-olefin with9-BBN and immediately subjected to cross-coupling with the cyclic keteneacetal phosphate in the reaction system, without being isolated.

In the present method for producing cyclic polyethers, when thesynthesis of alkylborane is carried out in situ as described above,isolation of alkylborane, which is unstable in air, is not required;therefore, such method is preferable. Also, by synthesizing alkylboranein situ, the production process may be simplified and the amount ofsolvent used for the purification steps may be cut down.

It goes without saying that the method for producing cyclic polyether ofthe present invention may also be performed by synthesizing, purifyingand separating the alkylborane first, and subjecting it tocross-coupling with the cyclic ketene acetal phosphate in the presenceof a basic solution and a PdCl₂ (dppf) catalyst. However, as describedpreviously, alkylborane is unstable in air, and therefore, in situsynthesis is preferable.

The invention of the present application is further described in detailby referring to the following Examples It should be understood that theinvention of the present application is not limited to these Examplesand that various embodiments are conceivable.

EXAMPLES Example 1 Suzuki Coupling-Reaction of Alkylborane with CyclicKetene Acetal Phosphate

9-BBN (2.6 equiv) was added to exo-olefin (IIa) at room temperature andreacted in THF at room temperature. To the resulting alkylborane (II),IM aqueous solution of NaHCO₃ (3 equiv), PdCl₂ (dppf) (10 mol %) andcyclic ketene acetal phosphate (III) (1.2 equiv) was added, and thereaction was carried out in DMF at room temperature for 20 hours.

The resulting product was compound (IV) and the yield was as high as97%.

Comparative Examples 1 to 4 Coupling Reaction of Alkylborane with CyclicKetene Acetal Phosphate (Comparison of Catalysts and ReactionConditions)

The reaction was carried out as described in Example 1, using variouscatalyst and reaction conditions.

Comparative Example 1

First, Pd(PPh₃)₄ (10 mol %) was used as a catalyst and the reaction wascarried out in DMF at 50° C.

Comparative Example 2

Next, the catalyst was changed to PdCl₂ (dppf) (10 mol %) and thereaction was carried out in DMF at 50° C.

Comparative Example 3

Further, the catalyst was changed to PdCl₂ (PCY₃)₂ (10 mol %) and thereaction was carried out in DMF at 50° C.

Comparative Example 4

Furthermore, the catalyst was changed toPd(OAc)₂/o-(di-t-butylphosphino)biphenyl, which was reported as beingeffective in proceeding the coupling reaction in high yield at roomtemperature (J. Am. Chem. Soc. 1999, 121, 9550-9561); the reaction wascarried out in dioxane at room temperature for 24 hours.

The yields of the reactions of Example 1 and Comparative Examples 1 to 4are shown in Table 1.

TABLE 1 Catalyst*¹ Reaction Conditions Yield (%) Example 1 PdCl₂(dppf)DMF, rt, 24 h 97 Comparative Pd(PPh₃)₄ DMF, 50° C. 20 h 87 Example 1Comparative PdCl₂(dppf) DMF. 50° C. 20 h 93 Example 2 ComparativePdCl₂(PCy₃)₂ DMF. 50° C. 20 h 50 Example 3 Comparative*² Example 4

dioxane, rt, 24 h 58 *¹catalyst: 10 mol %, NaHCO₃(aq.): 3 equiv.,Compound (III): 1.2 equiv. *²: 20 mol % Iigand used

From the above results, it is apparent that when PdCl₂ (dppf) is used asa catalyst, the product is obtained in high yield even at roomtemperature.

Example 2 Synthesis of FGH Ring of Gambierol

The FGH ring (compound (XI)) of gambierol was synthesized according tothe following scheme (4).

First, the compound (IV) obtained by the method of Example 1 washydroborated with BH₃ THF, and oxidized to give an alcohol (yield: 77%)stereoselectively. The alcohol was protected as a p-methoxybenzyl (PMB)ether, and desilylated, after which the resulting alcohol was oxidizedwith TPAP/NMO to give a ketone of compound (IX) In a yield of 83%.

Further, the PMB group was removed from the compound, reacted with EtSHand Zn(OTf)₂ and acetylated in situ to give a hemithioketal (X; yield:86%).

Compound (X) was oxidized and the resulting sulfone was reacted withMe₃Al to give compound (XI), the FGH ring of gambierol, in a yield of86%.

Industrial Applicability

As described above in detail, the present invention provides a methodfor producing cyclic polyether structures at room temperature, in highyields, in a convergent manner, which may be applied to the synthesis ofgambierol, without using an excessive amount of phosphate compounds.

What is claimed is:
 1. A method for producing cyclic polyethercompounds, comprising the cross-coupling reaction of alkylborane andcyclic ketene acetal phosphate in the presence of a basic aqueoussolution using palladium [1,1′-bis(diphenylphosphino)ferrocene]chlorideas a catalyst.
 2. The method for producing cyclic polyether compounds ofclaim 1, wherein a starting material for alkylborane and a reagent usedfor producing alkylborane are added to the reaction system prior to thecross-coupling reaction, thereby producing the alkylborane in situ,which is then reacted with cyclic ketene acetal phosphate in thepresence of a basic aqueous solution using palladium[1,1′-bis(diphenylphosphino)ferrocene]chloride as a catalyst.
 3. Themethod for producing cyclic polyether compounds of claim 1, wherein thealkylborane is obtained by the hydroboration of exo-olefin with 9-BBN.4. The method for producing cyclic polyether compounds of claim 1,wherein the basic aqueous solution is an aqueous solution of NaHCO₃. 5.The method for producing cyclic polyether compounds of claim 1, wherein1 to 2 equivalents of cyclic ketene acetal phosphate are added to 1equivalent of alkylborane.
 6. The method for producing cyclic polyethercompounds of claim 2, wherein the alkylborane is obtained by thehydroboration of exo-olefin with 9-BBN.
 7. The method for producingcyclic polyether compounds of claim 2, wherein the basic aqueoussolution is an aqueous solution of NaHCO₃.
 8. The method for producingcyclic polyether compounds of claim 3, wherein the basic aqueoussolution is an aqueous solution of NaHCO₃.
 9. The method for producingcyclic polyether compounds of claim 2, wherein 1 to 2 equivalents ofcyclic ketene acetal phosphate are added to 1 equivalent of alkylborane.10. The method for producing cyclic polyether compounds of claim 3,wherein 1 to 2 equivalents of cyclic ketene acetal phosphate are addedto 1 equivalent of alkylborane.
 11. The method for producing cyclicpolyether compounds of claim 4, wherein 1 to 2 equivalents of cyclicketene acetal phosphate are added to 1 equivalent of alkylborane.